Reno began as a railroad town. When the first transcontinental railroad reached the Truckee Meadows in 1868, a depot stood at this site. Myron Lake, who owned a toll bridge nearby, gave the Central Pacific Railroad land for it, and lots in the new town were auctioned on May 9.
A bigger Depot Hotel replaced the first wooden depot, burned in the Great Fire of 1879, was rebuilt, and burned again in May 1889. After that the railroad built a one-story brick station with a slate roof, and a new depot opened that December.
The current stucco depot was built by the Southern Pacific in 1926 in a Mission and Spanish Revival style. In the 2007 ReTRAC project the tracks were lowered below ground through downtown. The depot was added to the National Register of Historic Places on November 12, 2012, and Amtrak's California Zephyr stops here.